WO 2003/027080 describes that compounds such as 2-(2-arylmorpholin-4-yl)-1-methyl-1H-[4,4′]bipyrimidinyl-6-one represented by the following formula 43, and the like have tau protein kinase 1 inhibitory activity and are useful as a therapeutic drug for Alzheimer's disease and the like. It also describes that the compound of the formula 43 is synthesized from 2-chloro-1-methyl-1H-[4,4′]bipyrimidinyl-6-one of the formula 41 and an aryl-substituted morpholine compound of the formula 42 as starting materials.
wherein R is an aryl optionally having substituent(s) or a heteroaryl optionally having substituent(s).
Therefore, 2-chloro-1-methyl-1H-[4,4′]bipyrimidinyl-6-one of the formula 41 and the aryl-substituted morpholine compound of the formula 42 are used as intermediates for synthesizing a pharmaceutical agent.
According to WO 2004/085408, moreover, the compound of the formula 41 can be synthesized from ethyl 3-oxo-3-(pyrimidin-4-yl)propionate of the formula 44 via 2-mercapto-1-methyl-1H-[4,4′]bipyrimidinyl-6-one of the formula 45.

Therefore, the compound of the formula 44 is an important starting compound for synthesizing compounds such as 2-(2-arylmorpholin-4-yl)-1-methyl-1H-[4,4′]bipyrimidinyl-6-one etc.
Eur. J. Med. Chem., 31, 909-914 (1996) describes that 2-aryl-4-(2-hydroxyethyl)morpholine can be synthesized by heating phenacyl chloride, which is not substituted at the 4-position or has a chlorine atom or a methyl group at the 4-position, and N,N-diethanolamine in formic acid.
Chem. Ber., 115, 2635-2642 (1982) describes that 2-aryl-4-alkylmorpholine can be synthesized by heating 2-acetoxyacetophenone, which is not substituted at the 4-position or has a chlorine atom, a bromine atom or a methoxy group at the 4-position, and N-alkylethanolamine wherein the alkyl moiety is methyl, ethyl, propyl, isopropyl, butyl or benzyl, in formic acid.
Arch. Pharm. (Weinheim), 323, 41-42 (1990) describes that 2-phenyl-3,4-dimethylmorpholine can be synthesized by heating 2-bromopropiophenone and N-methylethanolamine in formic acid.
J. Med. Chem., 35, 3045-3049 (1992) describes that 2-aryl-4-propylmorpholine can be synthesized by reducing the carbonyl group of phenacyl bromide having a substituent at the 2- or 3-position, reacting the obtained compound with a base to give 2-aryloxirane, reacting the obtained compound with propylamine to give 1-aryl-2-(propylamino)ethanol, reacting the obtained compound with bromoacetyl chloride in the presence of potassium hydroxide to give 2-aryl-4-propylmorpholin-5-one, and reducing the obtained compound; and that 2-aryl-4-propylmorpholine can be synthesized by heating phenacyl bromide having a substituent at the 2- or 3-position or bromoacetylthiophene and N-propylethanolamine in formic acid.
J. Med. Chem., 18, 573 (1975) describes that 2-aryloxymethyl-4-alkylmorpholine can be synthesized by reacting 1-alkylamino-3-aryloxypropan-2-ol wherein the alkyl moiety is a hydrogen atom, methyl, isopropyl, allyl, cyclopentyl or benzyl with chloroacetyl chloride, reacting the obtained compound with sodium methylate, and reducing the obtained compound.
Chem. Pharm. Bull., 33, 3766 (1985) describes that 2-aryloxymethylmorpholine can be synthesized by reacting 2-(aryloxymethyl)oxirane with 2-aminoethyl hydrogensulfate in the presence of sodium hydroxide.
Heterocycles, 34, 1343 (1992) describes that 2-aryl-4-substituted or unsubstituted morpholine can be synthesized by reacting 2-bromoalkyl aryl ketone with N-substituted or unsubstituted benzylamine, reducing the carbonyl group of the obtained 2-aminoketone, and reacting the obtained 1-aryl-2-aminoethanol with oxirane; or by reacting 2-bromoalkyl aryl ketone with N-substituted or unsubstituted 2-aminoethanol, reducing the carbonyl group of the obtained 2-(2-hydroxyethyl)aminoketone, and reacting the obtained 1-aryl-2-(2-hydroxyethyl)aminoethanol with hydrobromic acid.
In addition, French patent No. 2285886 describes that a 2-arylmorpholine compound can be synthesized by, for example, reacting a compound of the formula:X—CH2—CH2—O—CH(Br)—CH2—Brwherein X is a halogen, with a compound of the formula:Ph-MgBrwherein Ph is a phenyl optionally having substituent(s). The optical isomer thereof can be obtained by subjecting the obtained racemic 2-arylmorpholine compound to optical resolution by a conventional method.
These methods are described as synthetic methods of racemic 2-aryl-4-substituted morpholine, and an efficient synthetic method of an optically active form thereof is not known. Particularly, as to 2-arylmorpholine, since the method for obtaining one enantiomer by optical resolution theoretically cannot achieve a yield exceeding 50%, because the other enantiomer cannot be efficiently converted to the racemate or the reverse enantiomer due to its chemical structure, this method is synthetically highly disadvantageous. Moreover, when N-unsubstituted morpholine is to be obtained from the N-substituted morpholines obtained by the methods described in Eur. J. Med. Chem., 31, 909-914 (1996); Chem. Ber., 115, 2635-2642 (1982); Arch. Pharm. (Weinheim), 323, 41-42 (1990); or J. Med. Chem., 35, 3045-3049 (1992), these references do not provide a synthetic example for N-benzyl group and the like permitting easy deprotection, or the yield is low, and in the case of a substituent showing a high yield, severe deprotection conditions are necessary. As such, they are not synthetically advantageous. J. Med. Chem., 18, 573 (1975); and Chem. Pharm. Bull., 33, 3766 (1985) that describe synthetic methods of N-unsubstituted morpholine do not describe a synthetic example of 2-arylmorpholine, and the synthesis method described in Heterocycles, 34, 1343 (1992) is problematic in that an isomer mixture is produced during the synthesis, identification of intermediate is complicated due to a treatment under strong acidic conditions in the final step, applicability to functional group is considerably limited, and the like, and French patent No. 2285886 poses concerns about the synthesis and handling of reaction intermediate.
Tetrahedron Asymmetry, Vol. 2, No. 2, pp 113-122, 1991 describes that S-(+)-4-fluorostyrene oxide (aka: (2S)-2-(4-fluorophenyl)oxirane) or R-(−)-4-fluorostyrene oxide can be synthesized by reducing 4-fluorophenacyl chloride, subjecting the obtained 2-chloro-1-(4-fluorophenyl)ethanol to optical resolution using lipase P, and reacting the obtained optically active 2-chloro-1-(4-fluorophenyl)ethanol with sodium hydroxide.
Tetrahedron, 58 (2002) 4693-4706 describes that optically active β-amino alcohol such as (1S)-1-phenyl-2-(benzylamino)ethanol and the like can be synthesized from optically active O-acetylmandelic acid.
However, it does not describe that optically active β-amino alcohol can be synthesized from arylacetyl chloride compound such as 4-fluorophenacyl chloride and the like via optically active 2-aryloxirane; and that optically active 2-aryl-substituted morpholine compound can be synthesized from optically active β-amino alcohol.
Some orotic acid esters are known, and some of them are commercially available. In addition, as methods for synthesizing orotate from orotic acid or its derivative, the following methods are known.
Yakugaku Zasshi, 84, 1057-1061 (1964) describes that ethyl orotate can be synthesized by heating orotic acid in a mixture of sulfuric acid and ethanol.
Scientia Pharmaceutica, 51, 374 (1984) describes that ethyl orotate can be synthesized by reacting orotonitrile with hydrogen chloride in ethanol to give imino ester, which is then hydrolyzed.
J. Org. Chem, 27, 3507 (1962) describes that methyl orotate can be synthesized by reacting orotic acid with thionyl chloride in the presence of a catalytic amount of pyridine to give orotyl chloride, which is then heated in methanol.
J. Org. Chem, 25, 1950 (1960) describes that butyl orotate can be synthesized by heating orotic acid in butanol in the presence of a catalytic amount of sulfuric acid.
International Journal of Pharmaceutics, 61, 43 (1990) describes that the corresponding orotate can be synthesized by heating orotic acid in alcohol saturated with hydrogen chloride or alcohol containing conc. sulfuric acid.
Bull. Soc. Chim. Belg., 1953, 611 describes that the corresponding orotate can be synthesized by heating orotic acid in methanol or ethanol saturated with hydrogen chloride.
Biochimica et Biophysica Acta., 23, 295 (1957) describes that the corresponding orotate can be synthesized by heating orotic acid in methanol or ethanol saturated with hydrogen chloride. This reference also describes that the corresponding orotate can be synthesized by reacting silver orotate with methyl iodide or ethyl iodide by the methods described in Ann. Soc. Chim. Milano, II, 18, 71 (1905); Chem. Ber., 63, 1000 (1930); or Chem. Ber., 64, 2683 (1931).
WO83/02891 describes that butyl orotate can be obtained at 56% by heating orotic acid together with butanol and sulfuric acid in toluene with dehydration for 12 hrs.
France Patent No. 1525298 describes that butyl orotate can be obtained by heating orotic acid together with butanol and p-toluenesulfonic acid in toluene with dehydration for 5 hrs, and further repeating (5 times) addition of p-toluenesulfonic acid, butanol and toluene and heating the mixture thereof, and that the corresponding amyl ester or isoamyl ester can be obtained by a similar method.
WO95/02407 describes that the corresponding orotate can be synthesized by heating methyl orotate in 2-ethylbutanol or 1-methylpropanol in the presence of sulfuric acid.
These methods are associated with the following problems. For example, Yakugaku Zasshi, 84, 1057-1061 (1964) requires complicated operation such as neutralization, extraction etc. Scientia Pharmaceutica, 51, 374 (1984) requires a long route and does not afford a direct synthesis. J. Org. Chem, 27, 3507 (1962) requires a long reaction time and multiple steps, and produces toxic gas such as hydrogen chloride, sulfur dioxide, methyl chloride and the like. J. Org. Chem, 25, 1950 (1960) requires a long reaction time and contains remaining starting materials. International Journal of Pharmaceutics, 61, 43 (1990); Bull. Soc. Chim. Belg., 1953, 611; and Biochimica et Biophysica Acta., 23, 295 (1957) require use of toxic hydrogen chloride and a long reaction time. Ann. Soc. Chim. Milano, II, 18, 71 (1905); Chem. Ber., 63, 1000 (1930); and Chem. Ber., 64, 2683 (1931) use a silver salt problematic in photostability and cost. WO83/02891 requires a long reaction time for a poor yield. France Patent No. 1525298 requires a long reaction time and complicated operation. WO95/02407 requires a long reaction time.
As a reaction for leading orotate to 2,6-dichloropyrimidine-4-carboxylate, Khimiya Seterotsiklicheskikh Soedinenii, 1986, 818 describes that n-butyl 2,6-dichloropyrimidine-4-carboxylate can be synthesized by chlorinating butyl orotate with phosphorus oxychloride. J. Org. Chem, 27, 3507 (1962) describes that methyl 2,6-dichloropyrimidine-4-carboxylate can be synthesized by chlorinating methyl orotate with phosphorus oxychloride. J. Org. Chem, 26, 2755 (1961) describes that methyl 2,6-dichloropyrimidine-4-carboxylate can be synthesized by chlorinating methyl orotate with phosphorus oxychloride.
As the dechlorination reaction of 2,6-dichloropyrimidine-4-carboxylate, Tetrahedron Lett., 1976, 693 has reported a dechlorination reaction of ethyl 2,6-dichloro-5-nitropyrimidine-4-carboxylate with magnesium oxide and triethylamine as a base in 2 steps while reducing nitro group.
As synthetic methods for pyrimidine-4-carboxylate other than the above-mentioned, J. Med. Chem, 20, 1312 (1977) has reported that methylpyrimidine-4-carboxylate can be synthesized by oxidizing 4-methylpyrimidine with selenium dioxide to give pyrimidine-4-carboxylic acid, and reacting the obtained compound with diazomethane. However, this method is problematic in that it uses highly toxic selenium compound.
While J. Org. Chem., 30, 2398 (1965) describes that methylpyrimidine-4-carboxylate can be synthesized by treating 5-bromo-2-methylthiopyrimidine-4-carboxylic acid with Raney-nickel, as described in J. Chem. Soc., 1953, 3129, to give pyrimidine-4-carboxylic acid, and heating the obtained compound in methanol in the presence of concentrated hydrochloric acid. This method is problematic in the availability of the starting materials.
As regards 3-oxo-3-(pyrimidin-4-yl)propionate, it is described in Khimiya Seterotsiklicheskikh Soedinenii, 1981, 530; and Khimiya Seterotsiklicheskikh Soedinenii, 1980, 822, and JP-A-52-105181 describes synthetic example of ethyl 3-oxo-3-(pyrimidin-4-yl)propionate, which comprises reacting methylpyrimidine-4-carboxylate with ethyl acetate in the presence of a base. However, no example is known where this compound was synthesized from orotic acid by the steps of the present invention.